tbuckley/cabot-search huggingface dataset:
John Launer: All’s well that ends well?
Authors: John Launer
Journal: BMJ (2023)

The relationship between doctors and their rulers has often been uneasy.The problem, as Marx might have pointed out, is largely one of social class.Members of the ruling class have generally held on to power through careers in politics, the military, and the exploitation of land and labour.By contrast, medicine has often been a route to social advancement for people from the middle classes (including immigrants), but it then gives practitioners power over vulnerable bodies.It's a power that everyone including rulers may find unnerving.If you really want to understand this relationship, however, you might want to read Shakespeare rather than Marx.To most people's surprise, one of his plays is a drama about the love-hate relationship between medicine and the aristocracy.It sits awkwardly in the canon, being neither a comedy nor a tragedy but having elements of both.As such, All's Well that Ends Well portrays almost every shade of the ambivalence that doctors and the establishment feel for each other.
Methenamine is as effective as antibiotics at preventing urinary tract infections
Authors: Helen Saul, Brendan Deeney, Samantha Cassidy, Jemma Kwint, Chris Harding
Journal: BMJ (2023)

The study Harding C, Mossop H, Homer T, et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non-inferiority trial. BMJ 2022;376:e068229. To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/methenamine-as-good-as-antibiotics-preventing-urinary-tract-infections/
Innovative strategies for photodynamic therapy against hypoxic tumor
Authors: Xiaotong Li, Lei Chen, Miaoting Huang, Shaoting Zeng, Jiayi Zheng, Shuyi Peng, Yuqing Wang, Hong Cheng, Shiying Li
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Photodynamic therapy (PDT) is applied as a robust therapeutic option for tumor, which exhibits some advantages of unique selectivity and irreversible damage to tumor cells. Among which, photosensitizer (PS), appropriate laser irradiation and oxygen (O2) are three essential components for PDT, but the hypoxic tumor microenvironment (TME) restricts the O2 supply in tumor tissues. Even worse, tumor metastasis and drug resistance frequently happen under hypoxic condition, which further deteriorate the antitumor effect of PDT. To enhance the PDT efficiency, critical attention has been received by relieving tumor hypoxia, and innovative strategies on this topic continue to emerge. Traditionally, the O2 supplement strategy is considered as a direct and effective strategy to relieve TME, whereas it is confronted with great challenges for continuous O2 supply. Recently, O2-independent PDT provides a brand new strategy to enhance the antitumor efficiency, which can avoid the influence of TME. In addition, PDT can synergize with other antitumor strategies, such as chemotherapy, immunotherapy, photothermal therapy (PTT) and starvation therapy, to remedy the inadequate PDT effect under hypoxia conditions. In this paper, we summarized the latest progresses in the development of innovative strategies to improve PDT efficacy against hypoxic tumor, which were classified into O2-dependent PDT, O2-independent PDT and synergistic therapy. Furthermore, the advantages and deficiencies of various strategies were also discussed to envisage the prospects and challenges in future study.
Efficacy and safety of bimekizumab in axial spondyloarthritis: results of two parallel phase 3 randomised controlled trials
Authors: Désirée van der Heijde, Atul Deodhar, Xenofon Baraliakos, Matthew A Brown, Hiroaki Dobashi, Maxime Dougados, Dirk Elewaut, Alicia M Ellis, Carmen Fleurinck, Karl Gaffney, Lianne S Gensler, Nigil Haroon, Marina Magrey, Walter P Maksymowych, Alexander Marten, Ute Massow, Marga Oortgiesen, Denis Poddubnyy, Martin Rudwaleit, Julie Shepherd-Smith, Tetsuya Tomita, Filip Van den Bosch, Thomas Vaux, Huji Xu
Journal: Annals of the Rheumatic Diseases (2023)

Axial spondyloarthritis (axSpA) is a complex disease with diverse manifestations, for which new treatment options are warranted. BE MOBILE 1 (non-radiographic (nr)-axSpA) and BE MOBILE 2 (radiographic axSpA (r-axSpA)) are double-blind, phase 3 trials designed to evaluate efficacy and safety of bimekizumab, a novel dual interleukin (IL)-17A and IL-17F inhibitor, across the axSpA spectrum.In parallel 52-week trials, patients with active disease were randomised 1:1 (nr-axSpA) or 2:1 (r-axSpA) to bimekizumab 160 mg every 4 weeks:placebo. From week 16, all patients received bimekizumab 160 mg every 4 weeks. Primary (Assessment of SpondyloArthritis international Society ≥40% improvement (ASAS40)) and secondary endpoints were assessed at week 16. Here, efficacy and treatment-emergent adverse events (TEAEs) are reported up to week 24.254 patients with nr-axSpA and 332 with r-axSpA were randomised. At week 16, primary (ASAS40, nr-axSpA: 47.7% bimekizumab vs 21.4% placebo; r-axSpA: 44.8% vs 22.5%; p<0.001) and all ranked secondary endpoints were met in both trials. ASAS40 responses were similar across TNFi-naïve and TNFi-inadequate responder patients. Improvements were observed in Ankylosing Spondylitis Disease Activity Score (ASDAS) states and objective measures of inflammation, including high-sensitivity C-reactive protein (hs-CRP) and MRI of the sacroiliac joints and spine. Most frequent TEAEs with bimekizumab (>3%) included nasopharyngitis, upper respiratory tract infection, pharyngitis, diarrhoea, headache and oral candidiasis. More fungal infections (all localised) were observed with bimekizumab vs placebo; no major adverse cardiovascular events (MACE) or active tuberculosis were reported. Incidence of uveitis and adjudicated inflammatory bowel disease was low.Dual inhibition of IL-17A and IL-17F with bimekizumab resulted in significant and rapid improvements in efficacy outcomes vs placebo and was well tolerated in patients with nr-axSpA and r-axSpA.
Abstract IA015: The tick-tock of epigenetic clocks in patients with cancer
Authors: Christin E. Burd
Journal: Cancer Research (2023)

Abstract There is a growing need to understand how aging influences cancer outcomes in older adults. Prior work shows that older adults with cancer would elect to forgo life-prolonging therapies that would lead to cognitive or physical disability. Here, we hypothesized that aging biomarkers would define individuals at risk for impairment and identify therapeutic regimens associated with accelerated aging. We first tested whether published epigenetic clocks would maintain validity in isolated CD3+ T cells. Potential advantages of using this approach in cancer patients include reduced sample complexity, the ability to survey aging in the context of clonal B cell expansions, and the critical importance of this cell population in cancer control. The Hannum, Horvath, GrimAge, PhenoAge, and PACE clocks increased with chronologic age in CD3+ T cells from 185 healthy donors. However, accelerated epigenetic age varied in PBMCs and CD3+ T cells isolated from the same blood sample. Next, we conducted a longitudinal analysis of adults ≥60 years of age newly diagnosed with non-small cell lung cancer (n=41) or hematologic malignancy (n=94). Standard clinical tools were used to assess fitness (ECOG performance, IADLs, SPPB), comorbidities, cognition (BOMC), and potential for therapeutic toxicity (CARG chemo-toxicity calculator). Relationships between these metrics and baseline CD3+ T cell epigenetic age were investigated. These analyses revealed a direct correlation between epigenetic age and increasing ECOG performance score. Cancer therapies, including high-dose chemotherapy, immunotherapies, and hypomethylating agents, significantly impacted patient epigenetic age. No relationship between outcome and baseline epigenetic age was observed in either population. These data support the use of the Hannum, Horvath, GrimAge, PhenoAge, and PACE clocks to measure aging in CD3+ T cells, though differences in PBMC and CD3+ T cell measurements suggest that the rate of epigenetic aging may differ in each sample type. The inability of epigenetic clocks to consistently measure physical function and cognition or predict patient outcomes implies that new clocks may be required to circumvent the heterogeneity of disease, therapies, and comorbidities in older adults with cancer. Citation Format: Christin E. Burd. The tick-tock of epigenetic clocks in patients with cancer [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA015.
Abstract B016: Aberrant age-related methylation leads to tumor predisposition in colorectal organoids
Authors: Daniel A. Petkovich, Rachael Powers, Yong Tao, Byunghak Kang, Nibedita Patel, Kathy Gabrielson, Rafael de Cabo, Stephen B. Baylin, Hariharan P. Easwaran
Journal: Cancer Research (2023)

Abstract Aging is one of the greatest risk factors for cancers, and epigenetic changes involving DNA methylation show close similarities during age-related cellular processes and tumor development. We have shown orthogonal relationships between the accrual of aberrant DNA methylation changes associated with cell division cycles during senescence and transformation. Consequently, we have hypothesized that while both senescent and proliferative aging cells coexist in the same tissues, the risk for cancer most likely comes from, and due to, epigenetic changes occurring in the latter, long-term, self-renewing cells. Using colon organoid models, we have studied the importance of genes undergoing DNA methylation mediated silencing during aging and their role in predisposing to tumorigenesis. Analyses of the in vivo and ex vivo aging-associated epigenetic/expression changes indicate the importance of age-related aberrant methylation in tumor promoting states. Citation Format: Daniel A. Petkovich, Rachael Powers, Yong Tao, Byunghak Kang Nibedita Patel, Kathy Gabrielson, Rafael de Cabo, Stephen B. Baylin, Hariharan P. Easwaran. Aberrant age-related methylation leads to tumor predisposition in colorectal organoids [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B016.
Abstract IA008: Role of race in accelerating progression of colorectal cancer
Authors: John M. Carethers
Journal: Cancer Research (2023)

Abstract African Americans present earlier in age and have higher incidence and mortality from colorectal cancer (CRC) compared to Whites. Socioeconomic inequality in the US that leads to higher comorbid illness among African Americans is likely a driver. Subsequent biological differences in African Americans include higher risk adenoma precursors that are more often proximally located in the colon, low microstatellite instability prevalence, and deficient immunologic profiles compared to Whites that contribute to cancer progression and outcome. Screening for CRC among African Americans had been recommended by some organizations to commence at age 45 or 40 years due to the observed epidemiology; this was not implemented until the US Preventive Services Task Force recommended CRC screening to commence at age 45 years for all races and ethnicities in 2021.Screening for CRC is one modality of intervention that can eliminate disparities; both colonoscopic and non-invasive screening have been shown to eliminate incidence and mortality differences between African Americans and Whites when using navigation. Recent gains in screening utilization among African Americans compared to Whites might be erased as a result of the COVID-19 pandemic. Navigated non-invasive CRC screening might help the unevenness of preventive services recovery from the pandemic if it can be fully implemented. Citation Format: John M. Carethers. Role of race in accelerating progression of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA008.
Abstract IA021: Studies of aging, morphology, and cancer in the domestic dog
Authors: Elaine A. Ostrander
Journal: Cancer Research (2023)

Abstract Each of the nearly 450 domestic dog breeds in existence today has a unique history and genetic profile. Early in the domestication process, dogs were bred to perform specific tasks such as herding, guarding and hunting. Later, fanciers developed hundreds of breeds, often displaying variation in body morphology, including shape and size, in addition to coat color, skull shape, leg length, etc. We are interested in understanding the genetic underpinnings of that variation, and applying those results to studies of growth regulation, normal and abnormal behavior and disease susceptibility. Dogs are a naturally-occurring model for many complex human disorders, including cancer. One in two dogs that live to be ten or older will develop cancer in their lifetimes, with most common human cancers occur spontaneously in dogs. This offers unique opportunities to study cancer susceptibility, progression and treatment response. The high rate of single types of cancer in some breeds, such as histiocytic sarcoma in Bernese Mountain Dogs or invasive bladder cancer in Scottish Terriers offers specific advantages for genetic studies that do not exist in human population studies. As with cancer, domestic dogs present interesting opportunities for studies of aging. Surprisingly, small breeds typically live longer than larger breeds, offering the chance to study the interaction between morphology and lifespan. To take advantage of these opportunities, we have assembled the largest and most diverse dataset of dog breeds and other canines to date, with canines originating from six continents, reflecting the extensive phenotypic variation and heritage that coalesce in modern dogs, and identified over 90 million single nucleotide variants. In this presentation we explore the genetics of cancer and aging in dogs, drawing parallels to the human condition. Citation Format: Elaine A. Ostrander. Studies of aging, morphology, and cancer in the domestic dog [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA021.
Abstract B010: Association between temporal muscle thickness and overall survival in non-small cell lung cancer patients with brain metastasis
Authors: Seung Ho Yang, Young Il Kim, Hyun Ho Kim, Byoung Yong Shim
Journal: Cancer Research (2023)

Abstract Temporal muscle thickness (TMT) has recently been suggested as a novel biomarker of sarcopenia in head and neck malignancies. However, few studies have evaluated TMT as a prognostic marker in patients with brain metastasis. This study investigated the association of TMT with overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastasis. The records of all NSCLC patients with brain metastasis between 2009 and 2018 at St. Vincent’s Hospital were reviewed retrospectively. A total of 221 patients met our eligibility criteria. In the group with TMT thicker than the median, OS was longer than the group with TMT thinner than the median (240 days versus 139 days, p = 0.014). In multivariate analysis, the thicker TMT group had longer survival (HR 0.73 CI 0.56–0.96, p = 0.024). Male (HR 1.58 CI 1.19–2.09, p = 0.002) and older age (≥ 65 years) (HR 2.05 CI 1.53–2.74, p &amp;lt; 0.001) also showed statistical significance. We also performed subgroup analysis in older patients (≥ 65 years). In this subgroup of 107 patients, the thicker TMT group also showed longer OS than the thinner TMT group (209 days versus 82 days, p = 0.009). Our findings suggest that TMT can be a useful biomarker for OS in NSCLC patients with brain metastasis. Citation Format: Seung Ho Yang, Young Il Kim, Hyun Ho Kim, Byoung Yong Shim. Association between temporal muscle thickness and overall survival in non-small cell lung cancer patients with brain metastasis [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B010.
Abstract IA016: Epigenetics mechanisms of tissue aging
Authors: Payel Sen
Journal: Cancer Research (2023)

Abstract Epigenetic alterations are one of the key hallmarks of aging. How epigenetic changes broadly affect euchromatin-heterochromatin balance, three-dimensional chromatin conformation, histone composition and global transcriptome in aging have been limitedly addressed. These outstanding questions are key to understanding the susceptibility of aged tissue to develop cancers, the incidence of which exponentially increases with age. Using murine liver as a model organ and an integrated multi-omics approach, we find that aged cells assume a repressed chromatin state characterized by condensed chromatin, broad heterochromatinization, and global suppression of the transcriptome. At the local level, there are site-specific chromatin openings with simultaneous derepression of genes. Our findings reveal a unique chromatin state in aging with opposing changes at the global and local levels. Citation Format: Payel Sen. Epigenetics mechanisms of tissue aging [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA016.
Abstract IA005: From hematopoiesis to immunity: Delineating the impact of aging on B-cell acute lymphoblastic leukemia progression
Authors: Curtis J. Henry
Journal: Cancer Research (2023)

Abstract The world’s aging population, those 65 and older, is projected to increase from 703 million people to 1.5 billion people by 2050. This great accomplishment comes with the added obligation of providing adequate healthcare for this vulnerable population given the number of diseases that manifest with age, including cancer. Chronic inflammation is a well-established hallmark of aging, and we have demonstrated that this state compromises hematopoiesis, notably the function of B-progenitor cells. Furthermore, we have shown that aging-associated functional declines in B-progenitor cells can be rescued with the anti-inflammatory cytokine interleukin-37, which also reduces the expression of checkpoint proteins on aged innate immune cells and augments the function of aged lymphocytes. Importantly, interleukin-37-mediated improvements in hematopoiesis and immunity suppress B-cell acute lymphoblastic leukemia (B-ALL) progression and enhance the protective capacity of aged chimeric antigen receptor (CAR) T-cells in murine models of B-ALL. Our results highlight the therapeutic potential of anti-inflammatory agents in treating hematological malignancies and suggest that combining anti-inflammatory cytokine treatment with immunotherapy strategies may represent a novel approach for treating aging-associated blood cancers. Citation Format: Curtis J. Henry. From hematopoiesis to immunity: Delineating the impact of aging on B-cell acute lymphoblastic leukemia progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA005.
Abstract IA023: Age against the machine: How the aging microenvironment drives tumor progression
Authors: Ashani Weeraratna
Journal: Cancer Research (2023)

Abstract Patients 65 and older account for 69% of all new cancer diagnoses. Melanoma is a deadly disease, with chances of survival for patients with stage IV disease totaling only 27%. Age-related changes- both secreted and biophysical- drive metastasis, immune cell recruitment, and changes in the vasculature. Age-related changes also impact the ability of tumor cells to respond to targeted therapy, and new data from our lab indicate this may be sex specific. Our recent studies also show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. We now show that age-induced changes in distal metastatic microenvironments promote efficient reactivation of dormant melanoma cells in the lung due to changes in Wnt signaling pathways. Overall, our studies argue for placing mechanistic studies of cancer biology into the context of aging. Citation Format: Ashani Weeraratna. Age against the machine: How the aging microenvironment drives tumor progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA023.
Abstract A026: History of blood transfusion and the risk of developing hematologic cancers in the United States: A cross-sectional study using the NHANES database. [R]
Authors: Amr Ebied, Jason Salemi, Chighaf Bakour, Nancy Gillis
Journal: Cancer Research (2023)

Abstract Blood transfusion has long been regarded as a determinant of cancer, plausibly because it influences inflammatory and immunological changes in the recipient's body. Recently, there has been evidence of a role of donor-derived malignancy in donors of autologous stem cell transplants, supporting the possible cancer-driving role of age-related clonal hematopoiesis. Given that routine blood transfusion is more ubiquitous than stem cell transplantation, we hypothesize an association between blood transfusion and the occurrence of hematologic malignancies. We conducted a secondary analysis using data from the 2017-2018 survey of the National Health and Nutrition Examination Survey (NHANES). A total of 4,917 participants were included in our final analytic sample, of whom 587 (11.9%) had ever received a blood transfusion. Out of the participants receiving a blood transfusion, six (1.1%) were diagnosed with hematologic cancer versus 9 (0.21%) from the non-transfusion group. Specifically, three (0.51%) participants from the transfusion group were diagnosed with leukemia versus 2 (0.046%) from the non-transfusion group. Using multivariable logistic regression, we have found that, after adjustment of other predictors, people with a history of blood transfusion were 4.08 (95%CI= 1.18-14.05), 2.09 (95%CI= 0.47-9.27), and 6.76 (95%CI= 1.13-40.44) times more likely to report a history of hematologic cancers, Hodgkin lymphoma, and leukemia, respectively than those who were never transfused. In conclusion, we found a possible significant association between blood transfusion and the risk of developing hematological cancers (particularly leukemia) in the United States. Prospective studies are needed to confirm the temporal sequence of blood transfusion and hematologic cancers in that regard. Citation Format: Amr Ebied, Jason Salemi, Chighaf Bakour, Nancy Gillis. History of blood transfusion and the risk of developing hematologic cancers in the United States: A cross-sectional study using the NHANES database. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A026.